Amantadine hydrochloride is a well known compound commercially available as Symmetrel.RTM. from E. I. du Pont de Nemours and Company, Wilmington, Del. Available dosage forms of Symmetrel.RTM. are soft gelatin capsules and oral syrup. U.S. Pat. No. 3,310,469 assigned to Du Pont, describes compositions containing amantadine.
Traditionally, when manufacturing oral pharmaceutical dosage forms such as soft gelatin capsules, for highly water soluble active ingredients, such as amantadine hydrochloride, the active ingredient is not dissolved but rather is suspended in a oleaginous mixture which is then used to fill the capsule. The suspensions used as fill material in the preparation of soft gelatin capsules must usually be sufficiently viscous to avoid the sedimentation of the suspended drug substance during the capsule filling. This process may take several hours. This fill variation is directly related to the dose variation from capsule to capsule and dependent upon the dynamic homogeneity of this suspension over the processing time.
Traditionally, the viscosity has been established with viscosity inducing agents either of mineral or vegetable origin such agents being either aqueous or oleaginous, such as: peanut, sesame, cottonseed, corn, sunflower, safflower, olive, and coconut oils, mineral oil, or waxes such as white wax, mono-, di-, triglycerides of edible oils, hydrogenated vegetable oil, beeswax, synthetic waxes of polyethylene glycol or their fatty acid esters. For examples of pharmaceutical compositions containing such viscosity inducing agents in soft gelatin capsules see: EP 184,942 which describes vitamin A soft gelatin capsules filled with wax mixtures in which active drug is suspended; and GE 1,282,853 which describes improved preparations for chloramphenicol suspended in a wax mixture of beeswax, hydrogenated soybean oil and hydrogenated vegetable oil.
In the case of Symmetrel.RTM. which has been commercially available from Du Pont, the innovator, for many years, soft gelatin capsules have always contained in addition to the soybean oil suspending vehicle, high melting point waxes and lipid employed as viscosity inducing agents. These waxes and lipids, in addition to inducing viscosity are water insoluble and coat the otherwise water soluble amantadine hydrochloride, reducing its rate of dissolution in aqueous media. Now, surprisingly, it has been found that in the case of Symmetrel.RTM., a viscosity inducing agent is not required and the elimination or reduction of the high melting point waxes or substitution in part with low melting point lipids significantly enhances the dissolution rate. Surprisingly, the content uniformity is maintained in the absence or reduction of these high melting point waxes or with the substitution in part with low melting point lipids.